Pain-Sensitive Cranial Structures: Chemical Anatomy
Central Sensitization and the Trigeminal System
Activation of nociceptive primary afferent fibers increases the excitability of higher-order neurons within the TNC (Burstein et al., 1998). In nontrigeminal pain models, depolarization of C fibers with chemical and inflammatory stimuli has resulted in several state changes. These include expansion of receptive field size (Woolf and King, 1990), lowering of thresholds for second-order neuronal activation in the dorsal horn (Woolf, 1984), recruitment of inputs from normally non-nociceptive fibers (Woolf and King, 1990), and heightened response to suprathreshold stimuli. Collectively, these changes are referred to as “central sensitization” and are reflected clinically in the pain-associated phenomena of spread of cutaneous sensitivity to uninjured areas, hyperalgesia (lowered pain threshold), and cutaneous allodynia (generation of a painful response by normally innocuous stimuli).
Features of central sensitization are observed in headache syndromes and probably contribute to the intensification and prolongation of head pain. For example, migraine pain frequently expands, as the headache develops, to involve half or at times the whole head. In addition, small, usually innocuous head movements (e.g., coughing or straining) become painful during and in the hours after resolution of a migraine attack. Chemical stimulation of nociceptors within the meninges lowers the activation threshold of second order neurons to low-intensity mechanical and thermal stimuli (Burstein et al., 1998).
In addition, noxious chemical dural stimulation lowers the threshold for generation of cardiovascular responses (such as blood pressure elevation) by previously innocuous skin stimulation (amamura et al., 1999). Evidence of central sensitization may be seen in humans as well. In a recent study of 42 migraine patients, repeated measurements of mechanical and thermal pain thresholds were performed in periorbital and forearm skin during and between acute headache attacks; 79% of subjects exhibited cutaneous allodynia (Burstein et al., 2000).
Central Inhibitory Modulation Of Trigeminal Nociception
Modulation within the central nervous system may be inhibitory as well. Defects of the intrinsic inhibitory system may also be important in the clinical evolution of chronic headache disorders. Within the TNC, the nociceptive signal can be modulated by inhibitory interneurons, within lamina II by projections from more rostral trigeminal nuclei (Kruger and Young, 1981) and the nucleus raphae magnus (Sessle et al., 1981), as well as by descending cortical inhibitory systems (Sessle et al., 1981; Wise and Jones, 1977).
Inhibitory GABAergic and enkephalinergic interneurons are likely to act not only on projection neurons (Fields and Basbaum, 1994) but also on the glutamate-containing terminals of primary afferent neurons, where they affect presynaptic inhibition (Iliakis et al., 1996). The most powerful descending inhibitory system is likely to involve projections from insular cortical and hypothalamic areas through the periaqueductal gray matter, and rostral ventral medial medulla to the superficial lamina of the TNC and the upper cervical dorsal horn (Messlinger and Burstein, 2000; Fields and Basbaum, 1994). Stimulation of the periaqueductal gray matter (Morgan et al., 1992), rostral ventral medial medulla (Lovick and Wolstencroft, 1979), areas of somatosensory cortex (Chiang et al., 1990), and hypothalamus (Rhodes and Liebeskind, 1978) suppresses nociceptive responses. The inhibitory interneurons within lamina II of the TNC receive input from descending excitatory serotonergic neurons from the periaqueductal gray matter and rostral ventral medial medulla (Fields and Basbaum, 1994).
Morphine administration increases the release of serotonin in the superficial lamina of the TNC and decreases presynaptic release of substance P. This is consistent with the hypothesis that morphine may activate the 5-hydroxytryptamine -mediated inhibition of nociception in the TNC and dorsal horn (Yonehara et al., 1990). Parabrachial areas (ventrolateral nuclei) also have direct and bilateral projections to all the subnuclei of the trigeminal brain stem nuclear complex (Yoshida et al., 1997). Stimulation of the parabrachial area suppresses both spontaneous and evoked firing in TNC nociceptive neurons (Chiang et al., 1994).
Conclusions
The neuroanatomical substrates of head pain are quite complex and still incompletely characterized. Headaches appear to develop through a cascade of events that are modulated by both suppressive and sensitizing systems. Derangement in these modulatory systems may underlie the development of chronic headache syndromes. A greater understanding of the functional anatomy and physiology of head pain holds the key to more specific and effective treatments.
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Editors: Silberstein, Stephen D.; Lipton, Richard B.; Dalessio, Donald J.